The production of the penicillamine by the hydrolytic decomposition of penicillin is known.
According to British Pat. No. 854,339, penicillins are converted by alkaline hydrolysis into the corresponding penicilloic acid. This is then isolated after extraction with an organic solvent such as n-butanol and by decarboxylation at increased temperature under lowered pressure converted into the corresponding penilloic acid.
The sodium salt of the penilloic acid is reacted with a mercuric halogenide, for example mercuric chloride, or a mercuric salt in the presence of halogen ions in aqueous solution. This results in the formation of a penicillamine-mercuric-halogenide-complex compound which is isolated by filtration and then thoroughly freed from the formed by-product penilloaldehyde and the inorganic salt by washing and suspending.
The complex is suspended in water and reacted with hydrogen sulfide. The mercury sulfide precipitates and is filtered off. The filtrate is concentrated by drying under vacuum. Penicillamine-hydrochloride is thus obtained. This is reacted with acetone for purification purposes. This results in the formation of penicillamine-isopropylidine-hydrochloride which is again converted to penicillamine-hydrochloride by means of a mineral acid such as hydrochloric acid at increased temperature.
In accordance with U.S. Pat. No. 3,281,461, a penicillin is hydrolized in alkaline medium to the corresponding penicilloic acid which, by means of a strong acid such as hydrochloric acid, is decarboxylated to the corresponding penilloic acid. By the reaction of the penilloic acid with mercuric chloride as the mercury (II)-salt, there is thus obtained the mercuric chloride complex of the penicillamine which is kept in solution.
The main interfering by-product is a penilloaldehyde, which, if not removed prior to the conversion of the mercuric complex, greatly reduces the recoverable yield of penicillamine. This removal can be accomplished by extraction by means of an organic solvent such as chloroform, ethyl acetate or methylene chloride, or by reaction with a carbonyl group-containing reagent such as hydroxylamine, semicarbazide or hydrazine. This compound forms with the penilloaldehyde an insoluble derivative at increased temperature which after renewed addition of mineral acid is filtered.
The solution freed from the penilloaldehyde is reacted with hydrogen sulfide, the resulting mercury sulfide is filtered off and the filtrate mixed with an organic solvent such as a short chain ester or alcohol, and the water is then removed by distillation. There is thus obtained crude penicillamine-hydrochloride. This can be purified through formation of the isopropylidene-derivative by reaction with acetone, and the said derivative decomposed with hydrochloric acid.
The known methods exhibit several disadvantages. In the first place it is necessary to operate with large volumes of reaction solutions since the utilized mercury compounds are relatively insoluble in water. Furthermore, it is necessary to operate with a mol ratio of mercury compound to penicilloic acid or penilloic acid of at least 1:1. This means that relatively large amounts of the mercury compounds must be utilized. This is disadvantageous since the mercury compounds are expensive throughout the world.